The neuroprotective roles for amyloid precursor protein (APR) and its soluble secreted fragment (sAPPa), a normal a-secretase cleavage product, have been demonstrated in culture systems against a broad spectrum of neuronal insults. Several protective roles observed in certain transgenic (Tg) mouse models overexpressing APP have also been inferred to sAPPa. The mechanisms underlying these actions, are however, scarcely studied. The objectives of this application are thus to investigate the molecular mechanisms of sAPPa's functions and to evaluate its beneficial effects on alleviating neuropathologies in mouse AD models. In preliminary studies, we demonstrated that mice or cells lacking APP are associated with increased stress kinase CDK5 activity and elevated tau phosphorylation, which can be restored by exogenous sAPPa. sAPPa possesses strong anti-apoptotic activity in NMDA-induced neuronal death which synergizes with IGF via a pathway involving Bcl-2. Importantly, we found neurogenic defect in young adult APP"'" mice and identified a neurotrophic function of sAPPain various cell/tissue cultures, which is synergized by EGF. Chronic infusion of sAPPa into adult mice reveals that the neuronal progenitor cells in the subventricular zone contain major binding sites for sAPPa in vivo. sAPPa preferentially binds to the lipid-enriched microdomains on the cell surface. Taken together, we hypothesize that sAPPa plays broad neuroprotective roles in preventing neuronal degeneration and death, and more intriQuinalv, a crucialrole in neuropenesis at both the prenatal and postnatal stages. sAPPa treatment in CNS at a proper dosage and timing will improve neuropathologies developed in mouse AD models. We therefore propose in Aim 1 to assess the roles of sAPPa in reducing neuropathologies in Tau Tg mouse model. We will test whether sAPPa treatment can reduce tau-phosphorylation and NFT formation, provide excitoprotection, and prevent memory loss using tau mutant (R406W) transgenic mice. Aim 2 will assess the potential roles of sAPPa in neurogenesis in APP"'* and APP/APLP2 double knockout mice. We will examine whether neurogenesis levels in these mice associate with their mortality, and whether chronic infusion of sAPPa can stimulate proliferation of neuronal progenitor/stem cells in these mice and rescue neurogenesis impairment. Aim 3 is to understand the molecular and cellular mechanism underlying the biological functions of sAPPa and to identify sAPPa-associated membrane protein(s). Molecular and cell biological approaches including crosslinking of membrane proteins with bound biotinylated sAPPa, lipid raft isolation, in combination with proteomic technologies, will be used to isolate and identify putative membrane-receptor(s) for sAPPa.. Our study will reveal novel physiological functions of APP/sAPPa as well as the underlying molecular mechanisms, and should shed light on potential therapeutic windows for sAPPa in the future.